PROJECT SUMMARY - SBIR R43/R44 Fast Track Application, FOA Number: PAS-18-187 The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer?s disease (AD) and AD related dementias (ADRD) with tau pathology. There is a critical unmet need for a disease-modifying drug (DMD) for AD. Chronic treatment strategies require safe, effective, and economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a DMD that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation. The Company is developing a small molecule DMD for AD that targets the initial step in tau aggregation leading to the formation of tau oligomers, the toxic tau aggregates responsible for neuronal loss and impairment of memory formation. We hypothesized that by targeting the first step in tau self-association all forms of tau aggregates should be reduced. In fact, we have demonstrated proof-of-concept in vivo, in a blinded study independently performed by Peter Davies, Ph.D., a thought leader in the field of tau biology and therapeutic discovery. The lead compound from our program inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD. Importantly, the lead has good CNS drug-like properties and has demonstrated a good safety profile in preliminary safety screens in vitro and in vivo. Here, we propose to advance this lead compound to IND enabling studies. During Phase I of the project our subcontractor, Albany Molecular Research, Inc. (AMRI, Albany, NY) will develop scale-up methods, analytical methods and synthesize 500 g of our lead compound (Phase I milestone 1). The program will be overseen by our Chemistry and Manufacturing Controls Consultant (Edward Cheesman, Ph.D.). This material will then be used by our subcontractor, Toxikon, Inc. (Bedford, MA). to carry out a single-dose rat PK study and 14 day non-GLP preliminary toxicology study in rat (Phase I milestone 2). Successful completion of the Phase I milestones will justify moving the program into Phase II, that includes carrying out all GLP genetic toxicity testing, safety pharmacology and general toxicology studies in two species, rat and dog. Oligomerix will manage the project, qualify the in vitro efficacy of the synthesized compound, and analyze and report the data. Throughout the program, Oligomerix will work with a regulatory consultant (Joseph Kozikowski, MD) to develop a regulatory strategy and to have a pre-IND meeting with the FDA. The proposed Aims will enable advancing the lead compound into pre-clinical development and will define the pharmacokinetic and toxicology studies that need to be performed to complete the IND package for the FDA. Developing a DMD for inhibition of tau oligomerization provides a crucial, novel, and viable approach to addressing the devastating impact of AD and ADRD.